Estrogen receptor beta variants and methods of detection thereof

Abstract

The present invention is based on sequencing genomic DNA from human chromosome 6 and cDNAs to define the genomic structure of estrogen receptor beta genes and novel polymorphism in the estrogen receptor gene / protein. Such polymorphism can lead to a variety of disorders that are mediated / modulated by a variant estrogen receptor, such as a susceptibility to cancer, osteoporosis, cardiovascular disorder, etc. Based on this sequencing approach, the present invention provides genomic nucleotide sequences, CDNA sequences, amino acid sequences and sequence polymorphism in the ESR-beta genes, methods of detecting these sequences / polymorphism in a sample, methods of determining a risk of having or developing a disorder mediated by a variant estrogen receptor and methods of screening for compounds used to treat disorders mediated by a variant estrogen receptor.

Description

[0001] The present application claims priority to provisional application U.S. Ser. No. 60 / 183,755, filed Feb. 22, 2000 (Atty. Docket CL000280-PROV).[0002] The present invention is in the field of disease detection and therapy. The present invention specifically provides the identification of previously unknown nucleic acid / amino acid polymorphisms within the estrogen receptor beta gene (ESR-beta) and the genomic sequence of this gene for use in the development of diagnostics and therapies for diseases and disorders mediated / modulated by the estrogen receptor.BACKGROUND OFF THE INVENTIONEstrogen Receptor[0003] The human estrogen receptor beta belongs to the nuclear hormone receptor family. Nuclear hormone receptors are a family of hormone-activated transcription factors that can initiate or enhance the transcription of genes containing specific hormone response elements.[0004] The ER protein consists of 595 amino acids with a molecular weight of 66 kDa, 8 transcribed exons, with six...

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Benefits of technology

[0028] The literature surrounding the involvement of estrogens in Rheumatoid arthritis is less clear than with osteoarthritis. Epidemiological studies suggests that RA is influenced by female sex hormones, by one study states that the use of oral contraceptives may postpone the onset of RA, but that estrogens alone no not alleviate the symptoms of RA (Bijlsma Am J Reprod Immunol 1992 Oct-Dec;28(3-4):231-4). Adjuvant oestrogen treatment does increase bone mineral density in postmenopausal women with RA, and may protect against osteophoresis which is often a complication of RA (van den Brink: Ann Rheum Dis 1993 Apr;52(4):302-5). While the study mentioned above indicated that estrogens did not alleviate RA symptoms, another study concluded that adjuvant estrogen therapy did not even improve the symptoms. One polymorphism has been reported in the estrogen receptor that seems to be associated with the age of onset of RA (Ushiyama Ann Rheum Dis 1999 Jan;58(1):7-10)

[0062] Combined with the use of a high density map of appropriately spaced, sufficiently informative SNP markers, association studies, including linkage disequilibrium-based genome wide association studies, will enable the identification of most genes involved in complex disorders, such as cardiovascular diseases, cancer etc. This will enhance the selection of candidate genes most likely to contain causative SNPs associated with a particular disease. All of the SNPs disclosed by the present invention can be employed as part of genome-wide association studies or as part of candidate gene association studies. The present invention advances the state of the art and provides commercially useful embodiments by providing previously unidentified SNPs in the estrogen receptor genes.

Problems solved by technology

However, a "healthy woman selection bias" is present in these studies and potentially may confound these results (estrogen takers have better weight control, exercise more, and smoke less than women who are not prescribed estrogen).

Estrogen replacement therapy is not without risk.

Controversy continues over whether estrogen replacement increases the risk of breast cancer, but some studies indicate risk is elevated by as much as 30%.

Based on these results, hormone replacement therapy is not recommended for secondary prevention of heart disease.

While the study mentioned above indicated that estrogens did not alleviate RA symptoms, another study concluded that adjuvant estrogen therapy did not even improve the symptoms.

Osteophorosis is a metabolic bone disorder that leads to bone fragility and subsequent risk of fracture.

All of these factors, with the exception of family history, have been shown to be directly associated with lifetime exposure to estrogen, increased hormone exposure being associated with increased risk of developing breast cancer.

In addition to these somatic mutations, some studies have pointed to a possible association between inherited DNA sequence changes and the development of breast cancer, but these studies are also controversial.

Although it remains somewhat controversial, studies suggest that use of tamoxifen may increase the chance of developing endometrial cancer.

In some instances, a variant form confers a lethal disadvantage and is not transmitted to subsequent generations of the organism.

For example, a heterozygous sickle cell mutation confers resistance to malaria, but a homozygous sickle cell mutation is usually lethal.

A nonsense mutation is a type of non-synonymous codon change that results in the formation of a stop codon, thereby leading to premature termination of a polypeptide chain and a defective protein.

Furthermore, in the case of nonsense mutations, a SNP may lead to premature termination of a polypeptide product.

Such variant products can result in a pathological condition, e.g., genetic disease.

For example, a SNP may inhibit splicing of an intron and result in mRNA containing a premature stop codon, leading to a defective protein.

Clinical trials have shown that patient response to treatment with pharmaceuticals is often heterogeneous.

Thus, HLA typing alone can significantly alter the estimate of risk for hemochromatosis, even if other family members are not available for formal linkage analysis.

Currently, however, it is not feasible to do SNP association studies over the entire human genome, therefore candidate genes associated with breast cancer are targeted for SNP identification and association analysis.

Furthermore, in the candidate gene approach, no assumptions are made about the extent of LD over any particular area of the genome.

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